Wassermann, Anne, Lounkine, Eugen, Whitebread, Steven, Chen, Shanni, Hughes, Kevin, Guo, Hongqiu, Kutlina, Elena, Fekete, Alexander, Urban, Laszlo, Klumpp, Martin and Glick, Meir (2013) Leaving the Lamp Post - A Fresh Perspective on the Targets of Natural Products and Marketed Drugs. Nature Chemical Biology.

Abstract

Chemical descriptors have been used exhaustively to predict protein targets for approved drugs. To predict truly novel and unexpected drug-target interactions in the future, compounds must be compared by other means than their chemical structure. We apply biological descriptors, i.e., HTS fingerprints (HTSFPs) for large-scale target prediction and the exploration of the mechanisms-of-action of natural products and drugs. HTSFP target predictions are orthogonal to prediction methods using chemical structure and outperform them for natural products that are often complex structures and chemical singletons. Large-scale target prediction reveals that clinically relevant target spaces covered by natural products and synthetic compounds are substantially different. A prospective application to ten experimental and marketed drugs identifies 49 previously unknown, in vitro confirmed small molecule-protein interactions. In multiple instances, newly identified targets that are phylogenetically and phylochemically distant to known targets have the potential to explain a molecule’s efficacy or side effects.

Item Type:	Article
Date Deposited:	27 May 2016 23:45
Last Modified:	27 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/20013